Method for producing optically active 2, 3-bisphosphinopyrazine derivative and method for producing optically active phosphine transition metal complex

a technology of phosphine and pyrazine, which is applied in the direction of group 5/15 element organic compounds, chemical instruments and processes, organic chemistry, etc., can solve the problems that the target isomer of a 2,3-bisphosphinepyrazine derivative having high optical purity cannot be obtained at good yield, and achieves high optical purity and high yield

Active Publication Date: 2020-03-19
NIPPON CHECMICAL IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010]Thus, an object of the present invention is to provide an industrially advantageous method for producing a 2,3-bisphosphinopyrazine derivative. More specifically, an object of the present invention is to provide a method for producing an optically active 2,3-bisphosphinopyrazine derivative, in which a (S,S) or (R,R) isomer of an optically active 2,3-bis(dialkylphosphino)pyrazine derivative having high optical purity can be obtained at high yield. Another object is to provide a method for producing an optically active phosphine transition metal complex useful as an anticancer agent in an industrially advantageous manner.

Problems solved by technology

Although the methods disclosed in Patent Literature 1 and Patent Literature 2 can provide the target 2,3-bis(tert-butylmethylphosphino)quinoxaline at good yield and high purity, a special cooling device is required to perform the aromatic nucleophilic substitution reaction at an extremely low temperature of −70° C. or less, and it also takes much time to cool the system to −70° C. or less and to increase the temperature to the temperature at which the subsequent deboranation reaction is performed, and thus the methods are industrially disadvantageous.
However, the problem with the method disclosed in Patent Literature 4 below is that the target (R,R) or (S,S) isomer of a 2,3-bisphosphinopyrazine derivative having high optical purity cannot be obtained at good yield.

Method used

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  • Method for producing optically active 2, 3-bisphosphinopyrazine derivative and method for producing optically active phosphine transition metal complex
  • Method for producing optically active 2, 3-bisphosphinopyrazine derivative and method for producing optically active phosphine transition metal complex
  • Method for producing optically active 2, 3-bisphosphinopyrazine derivative and method for producing optically active phosphine transition metal complex

Examples

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Effect test

example 1

Synthesis of (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline (a3)

[0072]

[0073]The air in a 300 mL four-neck flask which had been thoroughly dried was replaced with nitrogen, and then the flask was charged with 111.46 g (135.0 mmol) of a solution of 14.2% by mass (S)-tert-butylmethylphosphine-borane (a2) prepared above in tetrahydrofuran. The mixture was cooled to −10° C. under nitrogen atmosphere, and then 59.3 g of a 15% by mass n-butyllithium solution in hexane was added dropwise thereto over 1 hour. The mixture was aged for 1 hour at −10° C. to give solution B.

[0074]A 2,000 mL four-neck flask which had been thoroughly dried was separately prepared, and the air in the flask was replaced with nitrogen. Then the flask was charged with 8.97 g (45.0 mmol) of 2,3-dichloroquinoxaline (a1), tetrahydrofuran (81 ml), and 90 ml of N,N-dimethylformamide, and the mixture was cooled to −10° C. to give solution A.

[0075]Solution B was added to solution A at a constant rate over 40 minutes so ...

example 2

Synthesis of (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline (a3)

[0081]Reaction was performed in the same manner as in Example 1 except for changing the amount of tetrahydrofuran to 81 ml and the amount of N,N-dimethylformamide to 45 ml in solution A to give (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline (a3) (yield 69.4%). This crystal had a purity of 99.2% as measured by 31P NMR, and an optical purity of 99.5% ee or more.

example 3

Synthesis of (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline (a3)

[0082]Reaction was performed in the same manner as in Example 1 except for changing the amount of tetrahydrofuran to 81 ml and the amount of N,N-dimethylformamide to 20 ml in solution A to give (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline (a3) (yield 64.6%). This crystal had a purity of 99.1% as measured by 31P NMR, and an optical purity of 99.5% ee or more.

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Abstract

In the method for producing an optically active 2,3-bisphosphinopyrazine derivative of the present invention, an optically active 2,3-bisphosphinopyrazine derivative represented by the following formula (3) is produced by the step of: preparing solution A containing 2,3-dihalogenopyrazine represented by the following formula (1)
and a carboxylic acid amide coordinating solvent, lithiating an optically active R- or S-isomer of a hydrogen-phosphine borane compound represented by the following formula (2)
to give a lithiated phosphine borane compound; adding solution B containing the lithiated phosphine borane compound to the solution A to perform an aromatic nucleophilic substitution reaction; and then performing a deboranation reaction.
(For symbols in the formulas, see the description.)

Description

TECHNICAL FIELD[0001]The present invention relates to a method for producing a 2,3-bisphosphinopyrazine derivative. More specifically, the present invention relates to a method for producing a 2,3-bisphosphinopyrazine derivative useful as, for example, a ligand for a metal complex used as an asymmetric catalyst in an asymmetric synthetic reaction, and a ligand source for a transition metal complex used as an anticancer agent, and also relates to a method for producing a phosphine transition metal complex useful as an anticancer agent.BACKGROUND ART[0002]Reactions in organic synthesis catalyzed by a metal complex with an optically active phosphine ligand have long been known. These reactions are very useful, on which many research results have been reported. In recent years, ligands in which phosphorus atoms themselves are asymmetric have been developed. For example, Patent Literature 1 and Patent Literature 2 disclose an optically active 2,3-bis(dialkylphosphino)pyrazine derivative ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07F9/6509
CPCC07F9/650994
Inventor MAYAMA, DAISUKETAKESHITA, SATOSHITAMURA, KEN
Owner NIPPON CHECMICAL IND CO LTD
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